Ryo Niimi

Protection from sepsis-induced acute renal failure by adenoviral-mediated gene transfer of β2-adrenoceptor

BACKGROUND Sepsis is a common cause of acute renal failure (ARF) and results in a high mortality rate. The objective of the present study was to evaluate adenoviral transgenes containing the human beta(2)-adrenoceptor (adeno-beta(2)-AR) as a possible therapy for subjects at high risk for developing sepsis-induced ARF. METHODS An endotoxaemic rat model of ARF was induced by renal artery occlusion plus subcutaneous injections of Escherichia coli in 4-week-old Wistar rats. A subset of rats was given intraperitoneal injection of the adeno-beta(2)-AR gene. RESULTS Sepsis produced a depression in glomerular filtration rate and in the renal beta(2)-AR signalling system, which were both reversed by delivery of the beta(2)-AR gene. While delivery of the adeno-beta(2)-AR gene had no effect on recovery of cytokines and C-reactive protein in the systemic circulation, it did significantly depress (P < 0.01) the expression of the renal cannabinoid-1 (CB-1) receptor, CD14, toll-like receptor 4 (TLR4) and tumour necrosis factor (TNF)-alpha protein. Gene delivery also increased nitric oxide (NO) and decreased angiotensin II (Ang II). Finally, transfer of the beta(2)-AR gene also improved the survival of the rats exposed to sepsis-induced ARF. CONCLUSIONS A renal-specific over-expression of beta(2)-AR, resulting from gene delivery, appeared to modulate renal dysfunction and inflammation following sepsis by altering cAMP-PKA, CB-1 and CD14-TLR4-TNF-alpha pathways. In addition, gene delivery and activation of beta(2)-AR produced modulation of systemic NO and Ang II, which further protected against renal dysfunction. Administration of the Adeno-beta(2)-AR gene has potential as a therapeutic agent against ARF following the onset of sepsis.

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

The objectives of the present study were to define the contribution of β2-adrenoceptors(β2-ARs) agonists to renal physiology and to investigate whether over-expression of renal β2-ARs might be implicated in the pathogenesis of renal dysfunction in children as an adverse effect of β2-AR activation. The renal functional responses to the systemic injection of the β2-AR agonist terbutaline in Wistar rats over-expressing renal β2-AR were compared with those of nontreated rats. Furthermore, we evaluated intrarenal β2-AR expression in 34 children (age 2–15 y) and the changes in serum creatinine levels of 99 children (age 1–15 y) who received β2-AR agonists. The animal study showed that the suppression of glomerular function by terbutaline was associated with a reduction in systemic blood pressure and over-expression of renal β2-ARs. Moreover, in rats over-expressing renal β2-ARs, administration of terbutaline resulted in a high mortality rate after a lipopolysaccharide challenge. The clinical study showed that renal β2-AR expression gradually increased with age and was up-regulated by steroid therapy. These findings indicate that the renal dysfunction caused by β2-AR agonists can be explained, at least partly, by enhanced β2-AR expression in the kidney. This may have important implications for the use of β2-AR agonists in the treatment of sick children with, for example, steroid therapy or endotoxemia.

Adenoviral delivery of the β2-adrenoceptor gene in sepsis: a subcutaneous approach in rat for kidney protection

Successful gene therapy requires gene delivery that is efficient, has an optimal route of administration and has biosafety. The aims of the present study were to evaluate the safety and applicability of the subcutaneous delivery route for adenoviral transgenes containing the human beta(2)-adrenoceptor (adeno-beta(2)-AR) and to investigate whether this approach prevented renal dysfunction in a rat model of endotoxaemic shock induced by LPS (lipopolysaccharide). Subcutaneous administration of adeno-beta(2)-AR (a total of 10(10) viral particles) significantly increased beta-AR density in the kidney, lung and liver, but was without effect on physiological and plasma biochemical parameters. Moreover, this dose of virus did not cause any of the potential toxic responses of viral administration, such as inflammation and tissue TNF (tumour necrosis factor)-alpha expression. Although the LPS challenge caused a decrease in glomerular filtration rate, fractional excretion of sodium and renal beta-AR density in all groups, the reduction in renal function was significantly less in the rats given adeno-beta(2)-AR compared with non-treated rats. Thus, although further evaluation will be required, this initial study demonstrated that the subcutaneous injection of adeno-beta(2)-AR was efficient, comparatively non-pathogenic and potentially therapeutic to deal with acute renal failure associated with sepsis.